Oxa(thia)zolidine compounds, process for preparation thereof and anti-inflammatory agents

ABSTRACT

The present invention provides medicinal compositions characterized by comprising as the active ingredient either a compound represented by a formula [I] or a pharmaceutically acceptable composite thereof;  
                 
 
     [wherein X represents oxygen or sulfur; R 1  represents e.g., C 1-4  alkyl, phenyl optionally substituted, etc.; Q 1  represents spacer consisted of 0 to 3 carbon atoms; R 2  represents, e.g., phenyl optionally substituted; R 3  represents, e.g., hydrogen, C 1-4  alkyl, or a group represented by the following formulae; —CONH—R 6 ; R 4  and R 5  represent e.g., nitro, cyano, C 1-4  alkylcarbonyl, respectively];  
     in particular, medicine which is useful as therapeutic and/or protective drugs for inflammatory diseases and/or allergic diseases by improving sick conditions accompanied with the stimulated phospholipase A(2) activity.

FIELD OF THE INVENTION

[0001] The present invention relates to novel compounds, process forpreparation thereof, and medicinal compositions containing the activeingredient thereof, in particular, medicine comprising as the activeingredient either oxa(thia)zolidine compounds with phospholipase A(2)(hereinafter referred to as PLA(2)) inhibiting activity, or thepharmaceutically acceptable composites thereof.

BACKGROUND OF THE INVENTION

[0002] Inflammation is a series of defensive response process caused inthe tissues, induced by the applied injurious events (inflammatorystimuli) on any parts of a human body. When the tissues are damaged byinflammatory stimuli that could be caused by bacterial infections,immunological responses or physical injuries, the tissues respond (acuteinflammation) to the stimuli, followed by excluding the stimuli torepair the damages. Alternatively, if the exclusion is difficult, thedamages are progressed to induce continuously tissue swelling (chronicinflammation). Those inflammatory responses are well known to beassociated with several diseases, and various mediators are known to beassociated with each step during the inflammation process, constitutedwith activation of various cells and interactions with each other.

[0003] PLA(2) is a diverse class of enzymes, catalyzing preferentiallythe hydrolysis of the sn-2 acyl-ester of glycerophospholipids, that aremajor components of cell membranes, to liberate fatty acids. It is alsowell known that the PLA(2)s are responsible for deacylation-reacylationprocess required for cell membrane repair and maintenance, and thehydrolyzed products, as well as the further metabolites, are lipidmediators with strong diverse physiological activities. The liberatedproduct, arachidonic acid with some activity as mediator, is furthermetabolized in respective inflammation-associated cells toprostaglandins, thromboxanes, lipoxins, leukotrienes, etc., which inducecharacteristic physiological responses, respectively (Irvine, R.,Biochemical Journal 204: 3-16 (1982).). The other product,lysophosphatidylcholine not only plays roles as mediator, but also isutilized as a precursor of platelet activating factor (hereinafterreferred to as PAF). These lipid mediators play an essential role tomaintain homeostasis of living organisms, however, when they produced toexcessive amounts under sick conditions associated with inflammation,they could cause adversely effects. In fact, steroidal anti-inflammatorydrugs and various non-steroidal anti-inflammatory drugs (hereinafterreferred to as NSAIDs) are known to interfere with the eicosanoidcascade, have been widely used in clinical therapy. As PLA(2) ispositioned at the upstream of the eicosanoid cascade and is believed tobe the rate-limiting step in the generation of these lipid mediators,this enzyme has been expected to be the promising target for researchand development of novel anti-inflammatory drugs (Glaser, K. B.,Advances in Pharmacology 32: 31-66 (1995).).

[0004] Recently, numerous PLA(2)s have been identified and rapidlybecome a large superfamily consisted of more than 15 isozymes aresubdivided into four groups, on the basis of the protein structures andthe characteristics in the enzymatic activities(Dennis, E. A., Trends inBiochemical Science, 22: 1-2 (1997), and Balsinde, J. et al, AnnualReview of Pharmacology and Toxicology, 39: 175-189 (1999), etc.). Amongthem, it is noted that only the particular isozymes are shown highspecificity against arachidonyl-phospholipids, as well as the enzymaticactivity of the particular isozymes are selectively enhanced in a caseof inflammatory disorder. As the examples for suchinflammation-associated PLA(2)s, group IV-cytosolic PLA(2) (hereinafterreferred to as IV-cPLA(2); molecularweight 85 kDa) and the subtypes IIA,IID, V and X of secretory PLA(2) (hereinafter referred to as sPLA(2);molecular weight 14 kDa) may be exemplified. Among these, IV-cPLA(2) isparticularly considered as the responsible isozyme for producing thelipid mediators in the inflammatory diseases, which is supported byfindings from the ‘knockout’ (IV-cPLA(2)^(−/−))mice (Uozumi, N. et al,Nature 390: 619-622 (1997), Bonventre, J. V. et al, Nature 390: 622-625(1997), and Nagase, T. et al, Nature Immunology1: 42-46 (2000).).Therefore, the enhanced lipid mediators production under sick conditionscould be suppressed by inhibiting IV-cPLA(2) activity, therebyfacilitating remedy and/or prevention of the inflammatory diseases. Suchdiseases can be exemplified as following: anaphylaxis induced by variousinflammatory stimuli, septic shock, fever and pain; respiratorydiseases, such as bronchitis, pneumonia, and adult respiratory distresssyndrome; digestive diseases, such as inflammatory intestine disorder,Crohn's disease, ulcerative colitis, hepatitis, and nephritis;cardio-vascular diseases, such as vasculitis and arteriosclerosis;allergic inflammatory diseases, such as rhinitis, asthma and atopicsyndromes; and auto-immune diseases such as rheumatism;ischemia/reperfusion injuries, such as cerebral infarction andmyocardial infarction; nerve degenerative diseases, solar keratosis,psoriasis, and the like.

[0005] However, as no drug has been developed yet, which shows remedialeffects in the clinical therapies by inhibiting the enzyme activity, itis desired to develop such a new drug that can specifically andcomprehensively control the lipid mediators production in inflammatorydiseases, with excellent therapeutic and preventive effects.

[0006] In WO97/05135, as oxa(thia)zolidine compounds having activity ofinhibiting the PLA(2) activity, the compounds represented by thefollowing formula are disclosed.

[0007] In addition, 2-imino-4-oxothiazolidine compounds represented bythe following chemical formula is disclosed in WO93/10789.

[0008] Furthermore, it is described in Musser, J. H., et al, Journal ofMedicinal Chemistry 30: 2097-2093(1987). and GB 2183641 that thecompounds represented by the following chemical formula showanti-inflammatory activities, etc. by Leukotriene D₄ antagonisticeffects.

[0009] As for oxa(thia)zolidine compounds relevant to this invention,(4-methyl-5-phenyl-2-oxazolidinylidene)-propane dinitrile and theprocess for preparation thereof are disclosed in Huche, M. & Lhommet,G., Journal of Heterocyclic Chemistry 23 (3): 701-4(1986).

[0010] In addition, the compounds represented by the following chemicalformula are disclosed in the catalogue for manufactured goods dealt byChemDiv, Inc. or ChemStar, Ltd.

[0011] (wherein R represents ethyl or n-propyl)

[0012] Furthermore, the compounds represented by the following chemicalformula and the process for preparation thereof are disclosed in Hosomi,A., et al, Journal of Organic Chemistry 55: 5308-5310(1990).

[0013] (wherein R₂ represents hydrogen, methyl, ethyl or benzyl)

[0014] As for thiazolidine compounds relevant to this invention, thecompounds represented by following chemical formula and the use forphoto-polymerization initiator thereof are disclosed in Jpn. Pat. Appln.KOKAI publication No. Sho 53-152091.

[0015] However, it has not been known so far that those oxa(thia)zolidine compounds have PLA(2) inhibitory activity or anti-inflammatoryactivity.

DISCLOSURE OF THE INVENTION

[0016] As described above, it is understood that the enhanced PLA(2)activity plays a major role in the progress of various inflammatorydiseases. Therefore, an object of the present invention is to providemedicinal compositions, which is effective to remedy the inflammatorysick condition and to cure or prevent the relevant disease, and novelcompounds to be used for the medicinal composition.

[0017] As a result of the studies by the inventors of the presentinvention for aiming at achieving the aforementioned object, theoxa(thia)zolidine compounds, which had been known to have acaricidalactivity, have been found out also having inhibitory activity on PLA(2),thereby reaching the present invention.

[0018] The present invention is constituted with the following aspects(1) through (17).

[0019] (1) A medicinal composition characterized by comprising as theactive ingredient either a compound represented by a formula [I] or apharmaceutically acceptable composite thereof;

[0020] [wherein X represents oxygen or sulfur,

[0021] Q₁ represents —(CH₂)_(n)— or —CH═CH— (n represents 0, or aninteger ranging from 1 to 3),

[0022] R₁ represents hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl(optionally substituted by A₁)—C₁₋₆ alkyl or phenyl optionallysubstituted by A₁,

[0023] R₂ represents phenyl optionally substituted by A₁, naphthyloptionally substituted by A₁, indanyl optionally substituted by A₁,1,2,3,4-tetrahydronaphthyl optionally substituted by A₁, 5 to 7-memberedheterocyclic group optionally substituted by A₄ containing at least oneheteroatom selected from a group consisting of oxygen, sulfur andnitrogen,

[0024] R₃ represents hydrogen, C₁₋₆ alkyl optionally substituted by A₂,C₂₋₆ alkenyl optionally substituted by A₂, C₂₋₆ alkynyl optionallysubstituted by A₂, C₁₋₆ alkylcarbonyl optionally substituted by A₂, C₂₋₆alkenylcarbonyl optionally substituted by A₂, C₁₋₆ alkoxycarbonyloptionally substituted by A₂, C₂₋₆ alkenyloxycarbonyl optionallysubstituted by A₂, C₁₋₆ alkylsulfonyl optionally substituted by A₂, C₂₋₆alkenylsulfonyl optionally substituted by A₂, benzoyl optionallysubstituted by A₃, phenylsulfonyl optionally substituted by A₃, or agroup represented by the following formula;

[0025] (wherein Q₂ represents —CO—, —CS—, or —S(O)_(m)—,

[0026] R₆ represents hydrogen or C₁₋₆ alkyl,

[0027] R₇ represents C₁₋₆ alkyl optionally substituted by A₂, C₂₋₆alkenyl optionally substituted by A₂, C₂₋₆ alkynyl optionallysubstituted by A₂, C₃₋₇ cycloalkyl optionally substituted by A₄, C₅₋₇cycloalkenyl optionally substituted by A₄, C₁₋₆ alkylcarbonyl optionallysubstituted by A₂, C₁₋₆ alkylsulfonyl optionally substituted by A₂,phenyl optionally substituted by A₃, benzoyl optionally substituted byA₃, phenylsulfonyl optionally substituted by A₃, or 5 to 7-memberedheterocyclic group optionally substituted by A₄ containing at least oneheteroatom selected from a group consisting of oxygen, sulfur andnitrogen,

[0028] m represents 1 or 2),

[0029] R₄ represents hydrogen, cyano a group represented by thefollowing formula; —Q₃—R₈

[0030] (wherein Q₃ represents —CO— or —S(O)_(m)—,

[0031] R₈ represents amino, C₁₋₆ alkyl optionally substituted by A₂,C₂₋₆ alkenyl optionally substituted by A₂, C₂₋₆ alkynyl optionallysubstituted by A₂, C₁₋₆ alkoxy optionally substituted by A₂, C₂₋₆alkenyloxy optionally substituted by A₂, C₂₋₆ alkynyloxy optionallysubstituted by A₂, mono- or di-(C₁₋₆ alkyl)amino optionally substitutedby A₂, C₃₋₇ cycloalkyl optionally substituted by A₄, C₅₋₇ cycloalkenyloptionally substituted by A₄, phenyl optionally substituted by A₃,phenoxy optionally substituted by A₃, anilino optionally substituted byA₃, or 5 to 7-membered heterocyclic group optionally substituted by A₄containing at least one heteroatom selected from a group consisting ofoxygen, sulfur and nitrogen,

[0032] m represents 1 or 2),

[0033] R₅ represents nitro, cyano, or a group represented by thefollowing formula; —Q₃—R₈

[0034] (wherein Q₃ and R₈ is same as defined in the above description),

[0035] A₁ represents halogen, nitro, cyano, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, phenyl (optionally substituted byhalogen, C₁₋₆ alkyl or C₁₋₆ haloalkyl), pyridyl, thienyl, C₁₋₆ alkoxy,methylenedioxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfenyl, C₁₋₆ alkylsulfonyl,mono- or di-(C₁₋₆ alkyl)amino, C₁₋₆ haloalkoxy, benzyl, phenethyl,phenoxy, phenylthio, benzoyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl,C₁₋₆ haloalkylcarbonyl, C₁₋₆ haloalkoxycarbonyl, C₁₋₆ alkylcarbonyloxy,carbamoyl, or mono- or di-(C₁₋₆ alkyl)carbamoyl,

[0036] A₂ represents halogen, C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy,amino, mono- or di-(C₁₋₆ alkyl)amino, C₁₋₆ alkylcarbonyloxy, C₁₋₆alkoxycarbonyl, mono- or di-(C₁₋₆ alkyl)carbamoyl, mono- or di-(C₁₋₆alkyl)carbonylamino, morpholino, phenyl, or pyridyl optionallysubstituted by halogen,

[0037] A₃ represents halogen, hydroxy, oxo, mercapto, nitro, amino,cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, pyridyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,C₁₋₆ alkylsulfenyl, C₁₋₆ alkylsulfonyl, mono- or di-(C₁₋₆ alkyl)amino,C₁₋₆ haloalkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, carbamoyl,mono- or di-(C₁₋₆ alkyl)carbamoyl, and

[0038] A₄ represents halogen, hydroxy, oxo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkoxyC₁₋₆ alkoxy, C₁₋₆ alkylcarbonyl,C₁₋₆ alkylsulfonyl, or C₁₋₆ alkoxycarbonyl.].

[0039] (2) Compounds represented by a formula [I′] or pharmaceuticallyacceptable composites thereof;

[0040] (wherein X, Q₁, R₂, R₃, R₄ and R₅ are same as defined in thesection (1), R₁′ represents C₁₋₆ alkyl, C₁₋₆ haloalkyl,phenyl(optionally substituted by A₁)—C₁₋₆ alkyl, or phenyl optionallysubstituted by A₁;

[0041] with an exception of the following compounds, provisory;

[0042] X represents sulfur, both R₁′ and a group represented by R₂—Q₁represent phenyl, R₃ represents methyl, R₄ represents hydrogen, R₅represents benzoyl;

[0043] X represents oxygen, R₁′ represents methyl, a group representedby R₂—Q₁ represents phenyl, R₃ represents hydrogen, both R₄ and R₅represent cyano;

[0044] X represents oxygen, R₁′ represents methyl, a group representedby R₂—Q₁ represents phenyl, R₄ represents hydrogen, R₅ representsnitro.).

[0045] (3) A process for preparation, characterized by the reactionbismethylthioethylene compounds represented by the following formula[II];

[0046] (wherein R₅ is same as defined in the section (1), R₄′ is same asR₄ defined in the section (1) except for hydrogen),

[0047] with 2-aminoethanol compounds represented by the followingformula [III];

[0048] (wherein R₁, R₂, and Q₁ are same as defined as described above),

[0049] to obtain oxazolidine compounds represented by a formula [I-1];

[0050] (wherein R₁, R₂, R₅, R₄′, and Q₁ are same as defined as describedabove)

[0051] (4) A process for preparation, characterized by the reaction2-methylthio-2-thiazoline compounds represented by the following formula[IV];

[0052] (wherein R₁, R₂, and Q₁ are as defined in the section (1)described above),

[0053] with active methylene compounds represented by the followingformula [V];

R₄′—CH₂—R₅

[0054] (wherein R₅ is same as defined in the section (1), and R₄′ issame as defined in the section (3)),

[0055] to obtain thiazolidine compounds represented by a formula [I-2];

[0056] (wherein R₁, R₂, R₄′, R₅, and Q₁ are same as defined as describedabove).

[0057] (5) A process for preparation, characterized by the reactionoxa(thia)zolidine compounds represented by the following formula [I-3];

[0058] (wherein X, R₁, R₂, R₄, R₅, and Q₁ are same as defined in thesection (1)),

[0059] with halide compounds represented by the following formula [VI];

R₃′—Hal

[0060] [wherein R₃′ represents C₁₋₆ alkyl optionally substituted by A₂,C₂₋₆ alkenyl optionally substituted by A₂, C₂₋₆ alkynyl optionallysubstituted by A₂, C₁₋₆ alkylcarbonyl optionally substituted by A₂, C₂₋₆alkenylcarbonyl optionally substituted by A₂, C₁₋₆ alkoxycarbonyloptionally substituted by A₂, C₂₋₆ alkenyloxycarbonyl optionallysubstituted by A₂, C₁₋₆ alkylsulfonyl optionally substituted by A₂, C₂₋₆alkenylsulfonyl optionally substituted by A₂, benzoyl optionallysubstituted by A₃, phenylsulfonyl optionally substituted by A₃, or agroup represented by the following formula;

—S(O)_(m)—NR₆R₇,

[0061] (wherein R₆, R₇, and m are same as defined in the section (1)),

[0062] Hal represents halogen],

[0063] to obtain oxa(thia)zolidine compounds represented by a formula[I-4];

[0064] (wherein X, R₁, R₂, R₄, R₅, Q₁, and R₃′ are same as defined asdescribed above).

[0065] (6) A process for preparation, characterized by the reactionoxa(thia)zolidine compounds represented by the following formula [I-3];

[0066] (wherein X, R₁, R₂, R₄, R₅, and Q₁ are same as defined in thesection (1) described above), with compounds represented by thefollowing formula [VII];

R₇NCZ

[0067] (wherein R₇ is same as defined in the section (1),

[0068] Z represents oxygen or sulfur),

[0069] to obtain oxa(thia)zolidine compounds represented by a formula[I-5];

[0070] (wherein X, R₁, R₂, R₄, R₅, R₇, Q₁ and Z are same as defined asdescribed above).

[0071] (7) A composition comprising as the active ingredient at leastone selected from a group consisting of heterocyclic compoundsrepresented by the formula [I] and the pharmaceutically acceptablecomposites thereof.

[0072] (8) An inhibitor of phospholipase A(2) activity comprising as theactive ingredient at least one selected from a group consisting ofheterocyclic compounds represented by the formula [I] and thepharmaceutically acceptable composites thereof.

[0073] (9) A use of a composition for a mammalian which requiring remedyfor inflammatory diseases or disorders, where the composition ischaracterized by containing as the active ingredient at least oneselected from a group consisting of heterocyclic compounds representedby the formula [I] and the pharmaceutically acceptable compositesthereof.

[0074] (10) A method to remedy or reduce inflammatory diseases ordisorders, curing and/or preventing taking turn for the worth byadministering a medicinal composition, which is comprising an effectivedose of at least one selected from a group consisting of compoundsrepresented by the formula [I] and the pharmaceutically acceptablecomposites thereof to a mammalian requiring treatment.

[0075] (11) The method defined in the section (10); wherein theinflammatory diseases or the disorders are any of anaphylaxis, allergicinflammation, asthma, rhinitis, bronchitis, pneumonia, and adultrespiratory distress syndrome, inflammatory intestine disorder, Crohn'sdisease, ulcerative colitis, ischemia/reperfusion injuries, vasculitis,arteriosclerosis, hepatitis, nephritis, nerve degenerative diseases,arthritis, dermatitis, solar keratosis, psoriasis, septic shock andfever.

[0076] (12) The method defined in the section (10), wherein the progressof the sick condition is due to inflammatory disease or disorder that isaccompanied with the enhanced phospholipase A(2) activity.

[0077] (13) The method defined in the section (10), wherein theinflammatory disease or disorder is mediated by pro-inflammatory lipidmediators, such as arachidonic acid and the metabolites thereof, and/orlysophosphatidylcholines, and/or platelet activating factor (PAF).

[0078] (14) The method defined in the section (10), wherein thepro-inflammatory lipid mediators are suppressed by the inhibitor ofphospholipase A(2) activity.

[0079] (15) A use of a heterocyclic compound of the formula [I] formanufacturing of a medicinal composition, which is used for improvinginflammatory and/or allergic sick condition and/or sick conditionassociated with immunity, and/or for the remedy of such diseases anddisorders.

[0080] (16) A use of a composition as a medicine, where the compositioncontains as the active ingredient at least one selected from a groupconsisting of heterocyclic compounds represented by the formula [I] andthe pharmaceutically acceptable composites thereof.

[0081] (17) A use of a composition as an anti-inflammatory drug,anti-allergic drug and/or immune controlling drug, where the compositioncontains as the active ingredient at least one selected from a groupconsisting of heterocyclic compounds represented by the formula [I] andthe pharmaceutically acceptable composites thereof.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

[0082] In the compounds according to the present invention, which arerepresented by the formula [I] described above,

[0083] the “halogen” denotes fluoro, chloro, bromo, and the like,

[0084] the “C₁₋₆ alkyl” denotes methyl, ethyl, propyl, iso-propyl,butyl, iso-butyl, sec-butyl and tert-butyl, and the like,

[0085] the “C₂₋₆ alkenyl” denotes vinyl, 1-propenyl, iso-propenyl,allyl, 2-butenyl, and the like,

[0086] the “C₂₋₆ alkynyl” denotes ethynyl, propynyl, butynyl, or anisomer thereof, and the like,

[0087] the “C₁₋₆ alkylcarbonyl” denotes acetyl, ethylcarbonyl,propylcarbonyl, iso-propylcarbonyl, butylcarbonyl, iso-butylcarbonyl,sec-butylcarbonyl, tert-butylcarbonyl, and the like,

[0088] the “C₁₋₆ alkoxycarbonyl” denotes methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl,iso-butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, and thelike,

[0089] the “C₂₋₆ alkenylcarbonyl” denotes ethenylcarbonyl,vinylcarbonyl, allylcarbonyl, and the like,

[0090] the “C₁₋₆ alkoxy” denotes methoxy, ethoxy, propoxy, iso-propoxy,butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, andthe like,

[0091] the “C₂₋₆ alkenyloxy” denotes ethenyloxy, propenyloxy, allyloxy,hexenyloxy, and the like,

[0092] the “C₂₋₆ alkynyloxy” denotes acetynyloxy, propynyloxy,butynyloxy, hexynyloxy, and the like,

[0093] the “C₂₋₆ alkenyloxycarbonyl” denotes ethenyloxycarbonyl,propenyloxycarbonyl, allyloxycarbonyl, and the like,

[0094] the “C₁₋₆ haloalkyl” denotes chloromethyl, dichloroethyl,bromomethyl, trifluoromethyl, and the like,

[0095] the “C₁₋₆ alkylthio” denotes methylthio, ethylthio, propylthio,and the like, the “C₁₋₆ alkylsulfenyl” denotes methylsulfenyl,ethylsulfenyl, propylsulfenyl, and the like, and the “C₁₋₆alkylsulfonyl” denotes methanesulfonyl, ethanesulfonyl, propylsulfonyl,iso-propylsulfonyl, butylsulfonyl, sec-butylsulfonyl, pentylsulfonyl,hexylsulfonyl, and the like,

[0096] the “C₂₋₆ alkenylsulfonyl” denotes ethenylsulfonyl,propenylsulfonyl, allylsulfonyl, and the like,

[0097] the “C₃₋₇ cycloalkyl” denotes cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like,

[0098] the “C₅₋₇ cycloalkenyl” denotes cyclopentenyl, cyclohexenyl,cycloheptenyl, and the like,

[0099] the “C₁₋₆ alkylcarbonyl” denotes acetyl, ethylcarbonyl,propylcarbonyl, iso-propylcarbonyl, butylcarbonyl, sec-butylcarbonyl,pentylcarbonyl, hexylcarbonyl, and the like,

[0100] the “5- to 7-membered heterocyclic group” means a saturated orunsaturated heterocyclic group constituted by 5 to 7 atoms andcontaining at least one heteroatom selected from oxygen, sulfur andnitrogen, concretely, that includes tetrahydrofuranyl,tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl,tetrahydropyranyl, tetrahydrothiapyranyl, piperidinyl, pyrimidinyl,pyridyl, morpholino, and the like,

[0101] the “mono- or di-(C₁₋₆ alkyl)amino” denotes methylamino,dimethylamino, ethylamino, methylethylamino, hexylamino, and the like,

[0102] the “mono- or di-(C₁₋₆ alkyl)carbamoyl” denotes methylcarbamoyl,dimethylcarbamoyl, ethylcarbamoyl, methylethylcarbamoyl, and the like,the “mono- or di-(C₁₋₆ alkyl)carbonylamino” denotes acetylamino,diacetylamino, ethylcarbonylamino, acetylethylcarbonylamino, and thelike,

[0103] the “C₁₋₆ haloalkoxy” denotes chloromethoxy, dichloroethoxy,bromomethoxy, trif luoromethoxy, and the like,

[0104] the “C₁₋₆ haloalkoxycarbonyl” denotes chloromethoxycarbonyl,dichloroethoxycarbonyl, bromomethoxycarbonyl, trifluoromethoxycarbonyl,and the like,

[0105] the “C₁₋₆ alkylcarbonyloxy” denotes acetoxy, ethylcarbonyloxy,propylcarbonyloxy, butylcarbonyloxy, and the like, and the “C₁₋₆ alkoxyC₁₋₆ alkoxy” denotes methoxymethoxy, ethoxymethoxy, methoxyethoxy, andthe like.

[0106] The “pharmaceutically acceptable composite” denotes a compositecomprising the compound described above and an atoxic low-molecularcompound those interact with ionic, hydrogen or coordinate bonds eachother, at a particular combining ratio, and the compound should beliberated after the composite is solubilyzed in an aqueous solution.Specific examples for the pharmaceutically acceptable composite includesalts with ionic materials such as hydrochlorides, organic acids, aminoacids and the like, and solvates such as hydrates.

[0107] Now, the compounds represented by the formula [I] respectivelyinclude their structural isomers associated with at least the fourth andfifth positions of the oxa(thia)zolidine portion and their opticalisomers. In addition, when R₃ in the compound is hydrogen, the followingtautomers may be arisen.

[0108] It is to be noted that each of the compounds according to thepresent invention is not limited to the specific isomers, namelycompounds may include all possible isomers as well as possible racemicmodifications. Furthermore, depending on circumstances, the compoundsaccording to the present invention also may include the prodrugs and themetabolites of the compounds indicated above.

[0109] Now, the process for manufacturing the compounds according to thepresent invention is explained below.

[0110] Preparation Process 1:

[0111] The compounds represented by the formula [I-1], wherein Xrepresents oxygen and R₃ represents hydrogen, may be prepared by thereaction bismethylthioethylene compounds [II] with 2-aminoethanolcompounds [III], according to the following process;

[0112] (wherein R₁, R₂, R₄′, R₅ and Q₁ are same as defined above.).

[0113] The reaction may be carried out in an organic solvent for 1 toseveral hours at the temperature ranging from room temperature to theboiling point of the used solvent. As the organic solvent for the abovereaction, aromatic hydrocarbons such as benzene, toluene, xylene, andthe like; alcohols such as methanol, ethanol, and the like; polarsolvents such as DMF and DMSO; and the like may be used. Preferably, theabove reaction is desired to be carried out in alcohols as solvent atabout 100° C.

[0114] Preparation Process 2:

[0115] The compounds represented by the formula [I-2], wherein Xrepresents sulfur, R₃ represents hydrogen and R₄ represents asubstituent except for hydrogen, may be prepared by the reaction2-methylthio-2-thiazoline compounds [IV] with active methylene compounds[V], according to the following process;

[0116] (wherein R₁, R₂, R₄′, R₅ and Q₁ are same as defined above.).

[0117] The above reaction may be carried out by heating with an acidiccatalyst such as zinc chloride and the like, with or without solvents.Preferably, the above reaction is desired to be carried out by heatingwith zinc chloride as a catalyst at about 100° C. under nitrogen flow inan inert solvent such as benzene, toluene, DMF, and the like, whensolvent is used.

[0118] The 2-methylthio-2-thiazoline compounds represented by theformula [IV] may be prepared according to the process described in Jpn.Pat. Appln. KOKAI Publication No. Sho 63-41471.

[0119] Preparation Process 3:

[0120] The compounds represented by the following formula, wherein R₄represents hydrogen, may be prepared from the following formula [I-6]among of the compounds prepared according to either the preparationprocess 1 or the preparation process 2 as described above;

[0121] (wherein X, R₁, R₂, R₅ and Q₁ are same as defined above, R₉represents C₁₋₆ alkyl.)

[0122] Preparation Process 4:

[0123] The compounds according to the present invention, wherein R₃represents a substituent except for hydrogen, may be prepared by thereaction the following formula (I-3), which can be prepared according toeither the preparation process 1, the preparation process 2 or thepreparation process 3 as described above, with halide compounds (6), orwith either isocyanate compounds or isothiocyanate compounds representedby the formula (7);

[0124] (wherein X, R₁, R₂, R₃′, R₄, R₅, R₇,Z, and Q₁ are same as definedabove.).

[0125] The above reactions with halide compounds [VI] may be carried outin an organic solvent in the presence of a base for 1 to several hoursat the temperature ranging from −20° C., to the boiling point of theused solvent, and preferably from 0° C. to 70° C. As the organic solventfor the reactions, DMF, THF, DMSO, alcohols and the like maybe used. Asthe base for the reactions, sodium hydride may be used, or any ofalkoxides, triethylamine, 1,8-diazabicyclo(5,4,0)undecene-7 (hereinafterreferred to as DBU) and the like may be used as well.

[0126] The reactions with either a cyanate or an isothiocyanaterepresented by a formula [VII] may be carried out in an organic solventin the presence of a base for 1 to tens of hours at the temperatureranging from −20° C. to 60° C., and preferably from 0° C. to roomtemperature. As the organic solvent for the reactions, DMF, THF,chloroform, dioxane, benzene, and the like may be used. As the base forthe reactions, triethylamine, DBU, Pyridine and the like may be used.

[0127] After each reaction represented above, work-up may be employed asconventionally to obtain the objective compound.

[0128] The chemical structures of the compounds according to the presentinvention were determined by means of MASS, NMR, etc.

[0129] <Anti-inflammatory Agents>

[0130] The compound, represented by the formula [I] or thepharmaceutically acceptable composite thereof may be administrated tohumans and animals either directly or together with common carriers forpharmaceutical formulations. For applying the composite, theadministration route is not limited, and either route of systemicadministration or topical application, i.e. non-systemic administration,maybe selected appropriately upon necessity. Examples of the drug formfor medical treatment include pharmaceutical formulations for oraladministration such as tablets, capsules, granules, and powders,drinkable solutions, troches and the like; and parenteral solutions orsuspensions for intravenous injection, intramuscular injection,subcutaneous injection and the like. In addition, other administrationroutes, such as through rectum with suppositories, and through lung(through nose or inhalation through mouth) with aerosols, powderinhalants, etc. may be employed for applying the medicinal compositionaccording to the present invention. As pharmaceutical formulationssuitable for the topical application to penetrate the active ingredientinto the inflammatory regions through skins and mucosae, solutions,liniments, creams, emulsions, ointments and pastes, as well as dropssuitable for the treatment to eyes, ears and noses may be exemplified.There is no limit for the amount of the active ingredient to be applied,and therefore, the dose may be appropriately selected in a wide rangedepending upon the administration routes, the applied compounds, and thetreated patients, namely to humans or animals. In order to exert thedesired medicinal effectiveness, the compound of the present inventionis preferably administrated at a daily dose of 0.01-100 mg per kgbodyweight, with or without dividing the dose into several times. Forthe pharmaceutical formulations, it is preferable to contain the activeingredient in unit dosage form at a dose of 0.01 to 1,000 mg.

[0131] The pharmaceutical formulations for oral administrationcomprising the compound according to the present invention, such astablets, capsules, granules and drinkable solutions, may be preparedaccording to any of the conventional methods. More specifically, thetablets may be prepared by mixing the compound represented by theformula [I] or the pharmaceutically acceptable composite thereof withpharmaceutical fillers, such as starch, lactose, gelatin, magnesiumstearate, talc, gum arabic, and the like, and forming into tablets. Thecapsules may be prepared by mixing the compound represented by theformula [I] or the pharmaceutically acceptable composite thereof with aninactive pharmaceutical filler or diluent, and then charged intocapsules made of hard gelatin, soft capsules, or the like to. Themedicated syrups and elixirs for oral administration may be prepared bymixing the compound represented by the formula [I] or thepharmaceutically acceptable composite thereof with a sweetener such assucrose, an antiseptic such as Methylparaben and Propylparaben, acoloring agent, a flavor, and the like. Further, the parenteralpharmaceutical formulations of the compound of the present invention maybe prepared according to any of the conventional processes. For example,a parenteral pharmaceutical formulation may be prepared by dissolvingthe compound represented by the formula [I] or the pharmaceuticallyacceptable composite thereof with a sterilized liquid carrier. As theliquid carrier, water or saline solution may be preferably used. Inorder to provide the solution with a desired transparency, stability andcongeniality for the parenteral use, approximately 0.1 to 1,000 mg ofthe active ingredient may be dissolved in either water or an organicsolvent, and further dissolved with polyethylene glycol having amolecular weight of 200 to 5,000. For the preparation of the solution,it is preferable that a lubricant, such as polyvinylpyrrolidone,polyvinyl alcohol, sodium carboxymethyl cellulose, and methyl cellulose,is incorporated therein. Furthermore, a bactericide such as benzylalcohol, phenol and Thimerosal, and a fungicide may be incorporated intothe solution, in addition, an osmotic pressure conditioner, such assucrose and sodium chloride, a local anesthetic, a stabilizer, a bufferagent and the like may be incorporated into the solution upon necessity.More stable pharmaceutical formulation for parenteral use may beprovided by removing moisture in the frozen preparation following to thefilling, by means of freeze-drying technique known in the field.Accordingly, it is also possible to resolve the lyophilized powderthereof to prepare a pharmaceutical formulation just before the use.

[0132] Although the compounds represented by the formula [I] or thepharmaceutically acceptable composites thereof show to have stronginhibitory activity on the liberation of arachidonic acid duringinflammatory reaction, they have very weak inhibitory activity on theenzymatic hydrolysis due to secretary group IB-PLA(2) of porcinepancreas (hereinafter referred to as IB-sPLA(2); molecular weight 14kDa) when using a phospholipid, of which carbon in the oleic acidsubstituent at the second position being labeled with a radioactiveisotope, as the substrate. From this reason, an advanced safety can beexpected for the compounds represented by the formula [I] and thepharmaceutically acceptable composites thereof.

[0133] Since a part of the compounds of the present invention also haveherbicidal, insecticidal, acaricidal and/or fungicidal activities aswell, and they can be used as agrochemicals. In particular, an excellentperformance can be expected, as a drug provided by the compounds whichadditionally have inhibitory activity against fungi that causesinfectious diseases to mammals, such as pneumonia by anopportunistically fungus infection.

[0134] Among the compounds according to the present invention, thepreferable thiazolidine tautomer is trans, as for structural isomersassociated with the fourth and fifth positions of the oxa(thia)zolidineportion.

BEST MODE FOR CARRYING OUT THE INVENTION

[0135] Now, the present invention is further explained in detail withreference to the examples.

EXAMPLE 1

[0136] Preparation oftrans-5-(4-chlorophenyl)-4-methyl-2-(1-ethoxycarbonyl-1-nitromethylene)-thiazolidine

[0137] 9 g oftrans-5-(4-chlorophenyl)-4-methyl-2-methylthio-2-thiazoline, 4.7 g ofethyl nitroacetate, and 0.06 g of zinc chloride were added into a 100 mlcapacity of four neck flask, and the mixture was heated under nitrogenflow at the temperature ranging from 110˜130° C. for about five hours.After the completion of the reaction, the product mixture was dissolvedwith chloroform, washed with water, dried with magnesium sulfate, andthen condensed under reduced pressure. The oily product obtained waspurified by column chromatography to give 7.6 g of the title compound.

EXAMPLE 2

[0138] Preparation ofcis-5-(4-chlorophenyl)-4-methyl-2-(1-(4-methylphenylsulfonyl)-1-cyanomethylene)-oxazolidine

[0139] 1.5 g of1-cyano-2,2-bismethylthio-1-(4-methylphenylsulfonyl)-ethylene and 0.93 gof erythro-α-(1-aminoethyl)-4-chlorobenzyl alcohol were added into 20 mlof methanol and the mixture was refluxed for 3 hours. After thecompletion of the reaction, the reaction solution was condensed underreduced pressure. The product obtained was purified by columnchromatography to give 1.1 g of the title compound.

[0140] The representative compounds usable in the present inventionincluding the compounds prepared in the Examples described above arepresented in Tables 1 and 2. The abbreviations and the reference symbolsin the tables have the following meanings, respectively.

[0141] Me: methyl, Et: ethyl, Pr: propyl, Hex: hexyl, Hep: heptyl,Allyl: allyl, Ac: acetyl, Naph: naphthyl, Ph: phenyl, Bn: benzyl, Bz:benzoyl, THP: tetrahydropyranyl, n: normal, c; cyclo. TABLE 1

PhysicalConstant Compound R₁/ [ ]:MeltingPoint No. R₁ Q₁—R₂ R₃ R₄ R₅Q₁—R₂ ° C. 1-1 H Ph Et CN CN — Oily substance 1-2 H Ph H —COOMe CN —[155] 1-3 H Ph H —COOMe NO₂ — 1-4 H Ph Me CN CN — [129] 1-5 H Ph Me—COOMe CN — [129] 1-6 H 4-Cl-Ph H —COOEt NO₂ 1-7 H 4-Cl-Ph H —COOMe CN —[164.5] 1-8 H 4-Cl-Ph H —SO₂Ph CN — [254] 1-9 H 4-Cl-Ph Me CN CN — [209]1-10 H 2,6-diCl-Ph H CN CN — [273] 1-11 H 2,6-diCl-Ph H —CONH₂ CN —[288] 1-12 H 2,6-diCl-Ph H —COOEt CN — [232] 1-13 H 2,6-diCl-Ph H —COOMeCN — [279] 1-14 H 2,6-diCl-Ph H —SO₂Ph CN — [188] 1-15 H 2,6-diCl-Ph MeCN CN — Oily substance 1-16 H 2-MeO-Ph Me CN CN — Oily substance 1-17 H4-CN-Ph H CN CN — [234] 1-18 H 4-Me-Ph Me CN CN — Oily substance 1-19 H4-Ph-Ph H CN CN — Oily substance 1-20 H 4-Ph-Ph H —COOMe CN — [201] 1-21H Bn H CN CN — 1-22 H Bn H —COOMe CN — 1-23 H Bn H —COOMe NO₂ — 1-24 H—CH═CH-Ph H —COOMe CN — Oily substance 1-25 H —CH═CH-Ph H CN CN — 1-26 H

Me —COOMe CN — Oily substance 1-27 Me

H —COOMe NO₂ 1-28 Me

H —COOMe CN 1-29 Me 4-(4-Me-Ph)-Ph H —COOEt CN 1-30 Me 4-AcO-Ph H —COOEtNO₂ 1-31 Me 4-Ac-Ph Bz —COOEt NO₂ 1-32 Me 4-Allyl-Ph H —COOEt NO₂ 1-33Me 4-Br-Ph H —SO₂-(4-Cl-Ph) NO₂ 1-34 Me 4-CF₃CO-Ph H —COOEt NO₂ 1-35 Me4-CF₃-Ph Ac —COOEt CN 1-36 Me 4-CH₂Cl-Ph 3-MeOCH2O-Bn —COOEt NO₂ 1-37 Me4-Cl-Ph H —COAllyl —COAllyl 1-38 Me 4-Cl-Ph H —COOEt NO₂ 1-39 Me 4-Cl-PhH H NO₂ 1-40 Me 4-Cl-Ph H CN CN 1-41 Me 4-Cl-Ph H —SO₂-(4-Me-Ph) CN CISOily substance 1-42 Me 4-Cl-Ph H —SO₂-(4-Me-Ph) CN TRANS [205-207] 1-43Me 4-Cl-Ph H —COOEt CN 1-44 Me 4-Cl-Ph Et —COOEt CN 1-45 Me 4-Cl-Ph Bn—COOMe —COOMe 1-46 Me 4-Cl-Ph Bn —COOEt CN 1-47 Me 4-Cl-Ph —SO₂Me —COOEtCN 1-48 Me 4-Cl-Ph —COEt —COOEt CN 1-49 Me 4-Cl-Ph —COCH₂Cl —COOEt CN1-50 Me 4-Cl-Ph —SO₂Me —COOEt CN 1-51 Me 4-Cl-Ph Allyl —COOEt CN 1-52 Me4-Cl-Ph Bz —COOEt CN 1-53 Me 4-Cl-Ph —COCH₂Cl —COOEt CN 1-54 Me 4-Cl-Ph—COOEt —COOEt CN 1-55 Me 4-Cl-Ph —SO₂Ph —COOEt CN 1-56 Me 4-Cl-Ph—SO₂NMe₂ —COOEt NO₂ 1-57 Me 4-Cl-Ph —CH₂C≡CH H NO₂ 1-58 Me 4-Cl-Ph—CONH-cHex H NO₂ 1-59 Me 4-Cl-Ph H H NO₂ 1-60 Me 4-Me-Ph H—SO₂-(4-Me-Ph) CN 1-61 Me 4-Me-Ph H —SO₂-(4-Me-Ph) CN 1-62 Me 4-Et-Ph H—COOMe —COOMe 1-63 Me 4-MeOCO-Ph H —COOEt NO₂ 1-64 Me 4-Me-Ph —CO-AllylCN CN 1-65 Me 4-Me-Ph —COOEt CN CN 1-66 Me 4-Me-Ph —CONH-2-THP CN CN1-67 Me 4-Me-Ph 4-MeO-Bz CN CN 1-68 Me 4-Me-Ph 3-MeSO₂-Bz CN CN 1-69 Me4-Me-Ph Bn —COOEt CN 1-70 Me 4-Me-Ph Bz CN CN 1-71 Me 4-Me-Ph —CSNH-cHexCN CN 1-72 Me 4-Me-Ph H —COOEt CN CIS [135-137] 1-73 Me 4-Me-Ph —CH₂C≡CH—COOEt CN 1-74 Me 4-Me-Ph —CONH-cHex —COOEt NO₂ 1-75 Me 4-Me-Ph—CONH-cHep —COOEt CN 1-76 Me 4-Me-Ph —CON(-Me)-cHex —COOEt NO₂ 1-77 Me4-Me-Ph —CONH-(3-MeO-cHex —COOEt NO₂ 1-78 Me 4-Me-Ph —CONHCO-cHex —COOEtNO₂ 1-79 Me 4-Me-Ph —CONH—CH₂COOMe —COOMe NO₂ 1-80 Me 4-Me-Ph —CO-nPr—SO₂-(4-MeO-Ph) —SO₂-Ph 1-81 Me 4-Me-Ph —CONH-2-THP —SO₂-Ph NO₂ 1-82 Me4-Me-Ph —CONH-2-Py —SO₂-Ph NO₂ 1-83 Me 4-MeSO₂-Ph H —SO₂-(4-AcO-Ph) NO₂1-84 Me 4-n-Pr-Ph H —COOEt NO₂ 1-85 Me 4-Ph-O-Ph H —COOEt CN 1-86 Me4-Ph-Ph Ac —COOEt CN 1-87 Me 4-Ph-S-Ph H —COOEt CN 1-88 Me Bn H CN CN1-89 Me —C₂H₄-Ph H —CONHMe —CONHMe 1-90 Me —CH═CH-Ph H —CONHMe —CONHMe1-91 Me Naph H —COOMe —COOMe 1-92 Me

H —SO₂-Ph CN 1-93 Me

H —COOMe CN 1-94 Me

H —SO₂-Ph CN 1-95 Me

H —COOMe CN 1-96 Me

Me —COOMe CN 1-97 Et 4-Cl-Ph H —COOEt NO₂ 1-98 Et 4-Me-Ph H —COOEt —COMe1-99 Ph 4-PhO-Ph H —COOEt —COOEt 1-100 4-Me-Ph 4-Me-Ph H —COOEt —COOEt1-101 Bn Ph H —SO₂-Ph CN 1-102 —C₂H₄Cl 4-Cl-Ph H —SO₂-Ph —COOEt 1-103—CH₂Cl 4-Cl-Ph H —SO₂-Ph —COOEt 1-104 —CH₂F Ph H —COOEt —COOEt

[0142] TABLE 2

PhysicalConstant Compound R₁/ [ ]:MeltingPoint No. R₁ Q₁—R₂ R₃ R₄ R₅Q₁—R₂ ° C. 2-1 H Ph Et CN CN — 2-2 H Ph H —COOMe CN — 2-3 H Ph H —COOMeNO₂ — 2-4 H Ph Me CN CN — 2-5 H Ph Me —COOMe CN — 2-6 H 4-Cl-Ph H —COOEtNO₂ 2-7 H 4-Cl-Ph H —COOMe CN — 2-8 H 4-Cl-Ph H —SO₂Ph CN — 2-9 H4-Cl-Ph Me CN CN — 2-10 H 2,6-diCl-Ph H CN CN — 2-11 H 2,6-diCl-Ph H—CONH₂ CN — 2-12 H 2,6-diCl-Ph H —COOEt CN — 2-13 H 2,6-diCl-Ph H —COOMeCN — 2-14 H 2,6-diCl-Ph H —SO₂Ph CN — 2-15 H 2,6-diCl-Ph Me CN CN — 2-16H 2-MeO-Ph Me CN CN — 2-17 H 4-CN-Ph H CN CN — 2-18 H 4-Me-Ph Me CN CN —2-19 H 4-NO₂-Ph H —COOMe CN — 2-20 H 4-NO₂-Ph Me —COOMe CN — 2-21 H4-Ph-Ph H CN CN — 2-22 H 4-Ph-Ph H —COOMe CN — 2-23 H Bn H CN CN — 2-24H Bn H —COOMe CN — 2-25 H Bn H —COOMe NO₂ — 2-26 H —CH═CH-Ph H —COOMe CN— 2-27 H —CH═CH-Ph H CN CN — 2-28 H

Me —COOMe CN — 2-29 Me 4-Cl-Ph H —COOEt NO₂ TRANS n_(D) ^(22.5) 1.63422-30 Me 4-Cl-Ph H —COOEt NO₂ CIS n_(D) ²³ 1.6339 2-31 Me 4-Cl-Ph H—COOEt NO₂ CIS [203-205] DEC 2-32 Me 4-Cl-Ph H H NO₂ TRANS [148-150]2-33 Me 4-Cl-Ph H H NO₂ CIS [199-201] 2-34 Me 4-Cl-Ph H —COOEt CN CIS[121-123] 2-35 Me 4-Cl-Ph H CN CN 2-36 Me 4-Cl-Ph H —COOEt CN TRANS[228-231] 2-37 Me 4-Cl-Ph —CONH-cHex H NO₂ CIS [154-157] 2-38 Me 4-Cl-Ph—CONH-2-THP H NO₂ 2-39 Me 4-Cl-Ph —CONH-2-THP —COOEt CN 2-40 Me 4-Cl-PhH SO₂-(4-Me-Ph) CN 2-41 Me 4-Cl-Ph Et —COOEt CN TRANS [108-111] 2-42 Me4-Cl-Ph Allyl —COOEt CN CIS Oily substance 2-43 Me 4-Cl-Ph —CH₂C≡CH—COOEt CN TRANS n_(D) ²³ 1.6003 2-44 Me 4-Cl-Ph Me —COOEt CN 2-45 Me4-Cl-Ph —COEt —COOEt CN TRANS [168-170] 2-46 Me 4-Cl-Ph —SO₂Me —COOEt CNTRANS [210] 2-47 Me 4-Cl-Ph —SO₂Me —COOEt CN CIS [209-212] 2-48 Me4-Cl-Ph Me —COOEt —COOEt 2-49 Me 4-Cl-Ph Bn —COOEt CN TRANS Oilysubstance 2-50 Me 4-Cl-Ph Bn —COOEt CN CIS n_(D) ^(34.5) 1.5627 2-51 Me4-Cl-Ph —COCH₂Cl —COOEt CN TRANS [175-177] 2-52 Me 4-Cl-Ph —COCH₂Cl—COOEt CN CIS [112-115] 2-53 Me 4-Cl-Ph —COOEt —COOEt CN n_(D) ²⁰ 1.56902-54 Me 4-Cl-Ph —CONH-cHex —COOEt CN 2-55 Me 4-Me-Ph —CH₂C≡CH —COOEt CNn_(D) ^(21.5) 1.5329 2-56 Me 4-Me-Ph H —COOEt CN 2-57 Me Bn H CN CN 2-58Me —C₂H₄-Ph H —CONHMe —CONHMe 2-59 Me —CH═CH-Ph H —CONHMe —CONHMe 2-60Me

H —COOMe CN 2-61 Me

H —COOMe CN 2-62 Me

H —SO₂-Ph CN 2-63 Me

H —COOMe CN 2-64 Me

Me —COOMe CN 2-65 Me 4-Et-Ph H —COOMe —COOMe 2-66 Me Naph H —COOMe—COOMe 2-67 Me 4-Ph-Ph Ac —COOEt CN 2-68 Me 4-Me-Ph —CO-Allyl CN CN 2-69Me 4-Me-Ph —COOEt CN CN 2-70 Me 4-Me-Ph —CO-Pr-n —SO₂-(4-MeO-Ph) —SO₂-Ph2-71 Me 4-Me-Ph —CONH-2-THP CN CN 2-72 Me 4-Me-Ph 4-MeO-Bz CN CN 2-73 Me4-Me-Ph 3-MeSO₂-Bz CN CN 2-74 Me 4-Me-Ph Bz CN CN 2-75 Me 4-Me-Ph —SO₂Ph—COOEt CN 2-76 Me 4-Me-Ph —CONH-cHex —COOEt NO₂ 2-77 Me 4-Me-Ph—CONH-cHep —COOEt CN 2-78 Me 4-Me-Ph —CON(-Me)-cHex —COOEt NO₂ 2-79 Me4-Me-Ph —CONH-(3-MeO-cHex —COOEt NO₂ 2-80 Me 4-Me-Ph —CSNH-cHex CN CN2-81 Me 4-Me-Ph —CONH-2-THP —SO₂-Ph NO₂ 2-82 Me 4-Me-Ph —CONH-2-Py—SO₂-Ph NO₂ 2-83 Me 4-Me-Ph —SO₂NMe₂ —COOEt NO₂ 2-84 Me 4-Me-Ph—CONHCO-cHex —COOEt NO₂ 2-85 Me 4-Me-Ph H —COAllyl COAllyl 2-86 Me4-CF₃-Ph Ac —COOEt CN 2-87 Me 4-(4-Me-Ph)-Ph H —COOEt CN 2-88 Me4-Ph-O-Ph H —COOEt CN 2-89 Me 4-Ph-S-Ph H —COOEt CN 2-90 Me 4-Ac-Ph Bz—COOEt NO₂ 2-91 Me 4-AcO-Ph H —COOEt NO₂ 2-92 Me 4-MeOCO-Ph H —COOEt NO₂2-93 Me 4-MeSO₂-Ph H —SO₂-(4-AcO-Ph) NO₂ 2-94 Me 4-Br-Ph H—SO₂-(4-Cl-Ph) NO₂ 2-95 Me 4-n-Pr-Ph H —COOEt NO₂ 2-96 Me 4-CH₂Cl-Ph3-MeOCH₂O-Bn —COOEt NO₂ 2-97 Me 4-CF₃CO-Ph H —COOEt NO₂ 2-98 Me4-Allyl-Ph H —COOEt NO₂ 2-99 Me 4-Me-Ph —CONH—CH₂COOMe —COOMe NO₂ 2-100Et 4-Cl-Ph H —COOEt NO₂ 2-101 Et 4-Me-Ph H —COOEt —COMe 2-102 CF34-Me-Ph H —SO₂-Ph CN 2-103 CH₂F Ph H —COOEt —COOEt 2-104 CH₂Cl 4-Cl-Ph H—SO₂-Ph —COOEt 2-105 C₂H₄Cl 4-Cl-Ph H —SO₂-Ph —COOEt 2-106 Ph 4-PhO-Ph H—COOEt —COOEt 2-107 4-Me-Ph 4-Me-Ph H —COOEt —COOEt 2-108 Bn Ph H—SO₂-Ph CN 2-109 Me 4-Me-Ph

CN CN 2-110 Me Ph

—COOMe CN 2-111 Me 4-Me-Ph

—COOEt NO₂ 2-112 Me Ph

—COOEt —COOEt 2-113 Me 4-Me-Ph Me —CONHMe —CONHMe 2-114 Me —C₂H₄-Ph H—SO₂-Ph CN 2-115 Me —CH═CH-Ph H —SO₂-Ph NO₂

[0143] Next, the pharmaceutical formulation examples in the presentinvention are presented.

[0144] Pharmaceutical Formulation Example 1: Tablets Compositions Amount(g) Compound of the present invention 5 Lactose (The Pharmacopoeia ofJapan) 50 Corn starch (The Pharmacopoeia of Japan) 25 Crystallinecellulose 25 (The Pharmacopoeia of Japan) Methyl cellulose (ThePharmacopoeia of Japan) 1.5 Magnesium stearate 1

[0145] (The Pharmacopoeia of Japan)

[0146] A compound of the present invention, lactose, corn starch andcrystalline cellulose were incorporated thoroughly. The mixture wasformed into the granules with 5% aqueous solution of methyl cellulose,and the granules were passed through a sieve of 300 mesh and then driedcarefully. The dried granules were incorporated with magnesium stearateand then prepared into tablets according to the conventional method toobtain 1,000 tablets.

[0147] Pharmaceutical Formulation Example 2: Capsules CompositionsAmount (g) Compound of the present invention 10 Lactose (ThePharmacopoeia of Japan) 80 Starch (The Pharmacopoeia of Japan) 30 Talc(The Pharmacopoeia of Japan) 5 Magnesium stearate 1

[0148] (The Pharmacopoeia of Japan)

[0149] The compositions recited above were incorporated and crushed intofine particulates. The particulates of the mixture were then stirredthoroughly so as to obtain the homogenous mixture. The mixture was thencharged into capsules made of gelatin for oral administration use toobtain 1,000 pieces of two-pieces type gelatin capsules.

[0150] Pharmaceutical Formulation Example 3: Solution for InjectionCompositions Amount (g) Compound of the present invention 1 Polyethyleneglycol 4000 0.3 (The Pharmacopoeia of Japan) Sodium chloride (ThePharmacopoeia of Japan) 0.9 Polyoxyethylene sorbitan monooleate 0.4 (ThePharmacopoeia of Japan) Sodium metabisulfite 0.1 (The Pharmacopoeia ofJapan) Methylparaben (The Pharmacopoeia of Japan) 0.18 Propylparaben(The Pharmacopoeia of Japan) 0.02 Distilled water for injection useAppropriate (Final volume) 100 (ml)

[0151] The Parabens, sodium metabisulfite and sodium chloride weredissolved with approximately half of the final volume of distilled waterfor injection use at 80° C. while stirring. Then, the obtained solutionwas cooled down to 40° C. The compound of the present invention, andsubsequently polyethylene glycol and polyoxyethylene sorbitan monooleatewere added to the solution and dissolve therewith. Next, the restportion of the distilled water was added into the solution so as toadjust the volume to the final volume mentioned. The solution was thenfiltered through an appropriate filter to sterilize to obtain thepharmaceutical formulation of aqueous solution suitable for parenteraluse.

[0152] Pharmaceutical formulation Example 4: Ointment CompositionsAmount (g) Compound of the present invention 0.1 White soft paraffin 10

[0153] The compound of the present invention was incorporated into thebase material so as to be homogeneous therein.

[0154] Pharmaceutical formulation Example 5: Aerosol Compositions Amount(g) Compound of the present invention 0.25 Ethanol 29.75 Propelant22(Chlorodifluoromethane) 70

[0155] The compound of the present invention was incorporated intoethanol and then added with 1 part of Propelant 22 to obtain a mixture.The mixture was then cooled down to −30° C. and then placed in acharging apparatus. Next, an amount of the mixture required for aadministration was transferred into a stainless container and wasdiluted with the rest portion of the Propelant 22 to prepare thesolution for a erosol. The stainless container was then mounted with avalve unit to be ready for the administration.

[0156] Pharmaceutical Formulation Example 6: Dry Powder for InhalationCompositions Amount (g) Compound of the present invention 5 Lactose 95

[0157] The compound of the present invention was mixed with lactose toobtain a homogeneous mixture. The mixture was then charged into aninhaler for dry powder.

[0158] Pharmaceutical Formulation Example 7: Suppositories CompositionsAmount (g) Compound of the present invention 0.225 Saturated fatty acidglyceride 2.000

[0159] The compound of the present invention was passed through No. 60mesh U.S. sieve and then suspended in saturated fatty acid glyceridehaving been melted beforehand with minimum heat. The mixture was chargedinto a molding for suppositories with the indication capacity of 2 g andthen cooled.

[0160] Industrial Use

[0161] Pharmacological Test Example 1:

[0162] PLA(2) Activity

[0163] The PLA(2) activity was measured by quantitatively analyzing thefluorescent product of hydrolysis from1,2-bis-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indecene-3-undecanoyl)-sn-glycero-3-phosphocholine(hereinafter referred to bis-BODIPY®FL C₁₁-PC, Molecular probes, Inc.,B-7701) using activated U937 cells (human monoblastic lymphoma cellline) by inflammatory stimulus (Meshulam, T. et al., The journal ofBiological Chemistry 267 (30): 21465-21470 (1992); and Solito, E. etal., British Journal of Pharmacology 124: 1675-1683(1998).). Thesubstrate bis-BODIPY®FL C₁₁-PC is incorporated into cellular membranes,the proximity of the BODIPY®FL fluorophores on adjacent phospholipidacyl chains causes fluorescence self-quenching. Separation of thefluorophores upon hydrolytic cleavage of one of the acyl chains byPLA(1) or the PLA(2) results in increased fluorescence. In the activatedU937 cells by inflammatory stimuli, it is shown that this substrateshould be cleaved enzymatically by IV-cPLA(2) from the feature of itsbehaviors including sensitivity profiles against the inhibitors.

[0164] The human cell line U937 was purchased from Dai-NipponPharmaceuticals Co., Ltd. The cells were maintained by transferringevery 3-4 days into RPMI 1640 medium (Sigma Chemical Co., R6504)supplemented with heat-inactivated 10% fetal bovine serum (Fetal BovineSerum, Sigma Chemical Co., F 4135) in a 5% CO₂ humidified atmosphere at37° C. The cells were transferred into the culture medium describedabove, containing 1.2% (v/v) dimethylsulfoxide (hereinafter referred toas DMDO, Nacalai tesque Co., Ltd., D 134-45), and pre-cultured for 96 to120 hours so as to differentiate into the macrophage-like cells to beprovided for the assay. The macrophage-like cells were collected andwashed by centrifugation with the Assay medium (Dulbecco's phosphatebuffered saline (hereinafter referred to as PBS)-2.2 mM glucose-2.5 μMalbumin). Then, Phorbol 12-Myristate 13-Acetate (hereinafter referred toas TPA, Sigma Chemical Co., P 8139) was added to the Assay medium to be1×10⁻⁸M as the final concentration. Then, the macrophage-like cells werefurther cultured for an hour to be activated (Rzigalinski, B. A. &Rosenthal, M. D., Biochimica et Biophysica Acta 1223: 219-225 (1994);and Gonchar, M. V. et al., Biochemical and Biophysical ResearchCommunication, 249: 829-832 (1998).).

[0165] For preparing substrate liposome suspension, bis-BODIPY®FL C₁₁-PCwas combined with phosphatidylserine (Sigma Chemical Co., P7769) at 1:9molar ratio in chloroform, and dried under nitrogen flow. The driedmixture was suspended with the Assay medium at 100 μg/mL, voltexed andsonicated for an hour on ice under dark condition.

[0166] The test compound was dissolved with DMSO at 30 mM, and thesolution diluted with either DMSO or the Assay medium before additioninto the reaction mixture. The DMSO concentration in the reactionmixture was controlled so as to be no more than 0.1%. The 30-foldconcentration of test compound solution was put into each well of96-Wells Microplate, (Falcon, 3072) at a rate of 2.5 μL/well. To therespective well was added 25 μL/well of the activated U937 cellsuspension (6×10⁶ cells/mL), and the cells were pre-cultured for 120min. at 37° C. in a 5% CO₂ atmosphere incubator. 47.5 μL/well of thesubstrate liposome suspension with 1.5×10⁻⁶M A23187 (Sigma Chemical Co.,C 7522) was added into each well to prepare 75 μL/well of the totalreaction mixture, followed by culture for 30 min. under the sameconditions with shielding against light. 100 μL/well of 0.1% GEDTA(Dojindo Laboratories Co. Ltd., 348-01311) methanol solution was addedinto each well and mixed to stop the reaction. The increasedfluorescence of the hydrolysis product by the enzyme was determined bymeasuring the fluorescence emission intensity at 535 nm with excitationat 485 nm from the top side of each plate at 37° C., using a MultiFunctional Microplate Reader SPECTRA FLUOR PLUS (TECAN Austria GmbH).The measurements for the same test lot were carried out under the samesensitivity as the optimum gain condition for the first microplatemeasurement. In the test, each treatment was repeated three times, thereaction mixture plot without cells was used as the blank, andarachidonyl trifluoromethyl ketone (hereinafter referred to as AACOCF₃,Calbiochem-Novabiochem Corp., 100109) was used for the positive controltreatment. PLA(2) activity in each test plot was determined bysubtracting the mean value of the fluorescence emission intensity in theblank plot from that of each well, respectively. There was statisticallyno significant difference between the plots with and without 0.1% DMSO.In the pre-examination, the fluorescence emission intensity based on thesubstrate hydrolysis was increased linearly with time progression until90 min. Besides, hydrolysis as the basic metabolic activity, which wasmeasured as the enzymatic activity in the subcultured cells neitherbeing differentiated nor activated, without A23187 treatment condition,was shown about one seventh of that exerted by the activated cells.Thus, the difference obtained by subtracting the basic metabolicactivity from each enzymatic activity was determined as the inflammatoryactivated PLA(2) activity, and the inhibition rate was calculated by theinflammatory activated PLA(2) activity per the mean value of that of thecontrol plots with and without DMSO, for evaluating the activity of therespective test compounds. The inhibitory activity measured for therespective compounds of the present invention are shown in Table 3below, for example. TABLE 3 Compound No. Concentration (μM) Inhibition(%) 1-41 0.1 100 1-42 0.1 66 1-72 10 97 2-29 10 99 2-31 10 100 2-32 1098 2-33 1 84 2-34 10 98 2-36 10 97 2-37 1 87 2-43 10 100 2-45 1 55 2-460.1 82 2-47 10 98 2-49 1 89 2-55 1 70 AACOCF₃ 3 65

[0167] Pharmacological Test Example 2:

[0168] Mouse Ear Edema Induced by TPA

[0169] This test was carried out referring to the method of Carlson, R.P. et al. (Agents and Actions, 17(2): 197-204 (1985).) and the method ofChang, J. (European Journal of Pharmacology, 142: 197-205 (1987).). Morespecifically, 5 μg/20 μL of TPA (Sigma Chemical Co.), dissolved withethanol, was topically applied to the anterior and posterior surfaces ofthe right ear of an ICR-strain male mouse (6-7 weeks old). 6 hourslater, the thickness of each ear at the particular part was respectivelymeasured three times using a digimatic micrometer to calculate the meanvalue. Ear edema was determined by subtracting the mean thickness of theleft ear as without treatment from that of the right ear as TPA-applied.Topical application activity was evaluated by applying an acetonesolution of the compound of the present invention or 0.1% Tween80/acetone solution thereof similarly to the anterior and posteriorsurfaces of the right ear 30 min. before and 15 min. after theTPA-application. As the positive control, an acetone solution ofDexamathasone-21-acetate (hereinafter referred to as DEX-Ac, SigmaChemical Co., D 1881) and an acetone solution of indomethacin wereapplied similarly as for the compound of the present invention. Oraladministration activity was evaluated by administrating 0.2% Tween 80suspension of the compound of the present invention forcibly andperorally to the mouse an hour prior to the TPA-application. As thepositive control, 100 mg/kg of Hydrocortisone (Sigma Chemical Co., H4001) suspension was applied to the mouse similarly as for the compoundof the present invention. By the treatment with the compounds of thepresent invention, anti-inflammatory activities, for example as shown inTable 4, were measured for the respective compounds. Furthermore, it wasnoted that the mice of both DEX-Ac administration group and indomethacinadministration group showed intoxicated symptoms and their body weightwere reduced after 24 hours. On the contrary, neither remarkableintoxicated symptom, nor significant change in their body weight wasobserved in the mice in the each group applied with the compounds of thepresent invention. TABLE 4 Dose (mg/μL/ Ear Edema Compound No. ear × 2)Inhibition (%) 1-41 1 mg/40 μL 80.5 2-29 0.3 mg/20 μL   78.6 2-37 1mg/40 μL 35.2 2-43 0.3 mg/20 μL   75.4 2-49 1 mg/40 μL 65.9 DEX-Ac 1mg/20 μL 79.6 Indomethacin 3 mg/40 μL 63.5

[0170] Pharmacological Test Example 3

[0171] Mouse Delayed Contact Dermatitis Induced by Picryl Chloride

[0172] This pharmacological test was carried out referring to the methodof Asherson, G. L. & Ptak, W. (Immunology, 15: 405-416 (1968).) and themethod of Jun Hiroi (Folia Pharmacology of Japan, 86: 233-239 (1985).).More specifically, hairs on the abdomen of an ICR-strain male mouse wereremoved using an electric clipper and an electric shaver. Then, 0.1 mLof 7% ether solution of picryl chloride (Tokyo Kasei Kogyo Co., Ltd., C0307) was applied onto the abdomen for sensitization. On the sixth dayafter the sensitization, 20 μL/ear of 1% olive oil solution of picrylchloride was topically applied to the anterior and posterior surfaces ofboth ears of the mouse to induce contact dermatitis (first induction).Before and 24 hours after the induction, the thicknesses of theparticular parts on the both ears were measured three times,respectively, using a digimatic micrometer (Mitsutoyo Co., Ltd.) to workout the average values. Ear edema of the both ears was respectivelydetermined by subtracting the average thickness of the each ear beforethe induction from that on 24 hours after the induction, so that agrouping was carried out to separate the appropriate individuals. On thefourth day after the first induction, the hairs on the abdomen wereremoved again, and 0.1 mL of 7% ethanol solution of picryl chloride wasapplied thereto for additional sensitization. The contact dermatitis forevaluating activity was induced by re-applying 20 μL/ear of 1% olive oilsolution of picryl chloride to the anterior and posterior surfaces ofboth ears (second induction) on the seventh day after the additionalsensitization (on the 18th day after the first sensitization). Theactivity of each compound of the present invention was evaluated as theinhibition on the contact dermatitis as compared with that of thevehicle applied control. That is, the thicknesses of the particularportions of the both ears were measured respectively three times with adigimatic micrometer to work out the mean values before, 24 hours and 48hours after the second induction. Ear swelling was determined bysubtracting the ear thickness before the second induction from that on24 hours and 48 hours after the second induction, respectively. Topicalapplication activity was evaluated by applying 25 μL of the acetonesolution of the compound of the present invention similarly to theanterior and posterior surfaces of the right ear one hour before and 16hours after the second induction. As the positive control, 0.02 mg/20 μLof acetone solution of Dexamethasone (hereinafter referred to as DEX,Wako Pure Chemical Industries Ltd., 047-18863) was applied similarly asfor the compound of the present invention. With respect to theinhibitory activity in topical application tests, the topical activitywas determined by the inhibition of the applied right ear edema, and thetranslocation and distribution property was determined by the activityonto the swelling of non-treated left ear. Oral administration activitywas evaluated by administrating 0.5% methyl cellulose suspension of thecompound of the present invention forcibly and perorally to the mouse anhour before and 16 hours after the second induction. As the positivecontrol, 20 mg/kg of Prednisolone (Sigma Chemical Co., P 6004)suspension was administrated similarly as for the compounds of thepresent invention. With respect to the compounds of the presentinvention, the anti-allergic activities as shown in Table 5 weremeasured. Furthermore, it was noted that the mice of DEX administratedgroup group showed intoxicated symptoms and their body weight werereduced significantly 48 hours after the second induction. On thecontrary, neither remarkable intoxicated symptom, nor significant changein their body weight was observed in the mice in the each group appliedwith the compounds of the present invention. As the examples, the bodyweight changes in the mice for 48 hours after the second induction whenthey were administrated with the compounds shown in Table 5 are shown inTable 6. TABLE 5 Dose Ear swelling after 24 hours Compound (mg/25 μL/Right (Applied) Left (Not applied) No. ear × 2) (Mean ± S.E., mm) (Mean± S.E., mm) Vehicle — 0.299 ± 0.006 0.284 ± 0.008 Control 2-29 1.5 0.261 ± 0.012 0.243 ± 0.020 DEX 0.02 0.057 ± 0.009 −0.005 ± 0.033 

[0173] TABLE 6 Body weight Change in body weight 48 Dose beforeinduction hours after induction Compound (mg/ (Mean ± S.E.) (Mean ±S.E.) No. ear × 2) (g) (g) (%) Vehicle — 34.45 ± 0.85 −0.45 ± 0.20 −1.29± 0.59 Control 2-29 1.5 31.52 ± 0.35 −0.06 ± 0.15 −0.20 ± 0.48 DEX 0.0232.84 ± 0.73 −1.42 ± 0.20 −4.30 ± 0.59

[0174] Pharmacological Test Example 4:

[0175] Acetic Acid Wirthing

[0176] This test was carried out referring to the method of Inoue, K.,Motonaga, A. & Nishimura, T (Arzneimittel Forshung/Drug Research, 41(1): 235-239 (1991)). More specifically, 7.5 mL/kg of 0.9% acetic acidsolution was injected intraperitoneally into an ICR-strain male mouse (5to 7 weeks old), and the induced writhes (characteristic behaviors ofconvulsive contracting the abdomen, twisting the body and/or extendingthe legs) were observed. Number of writhes of each mouse was measuredduring 10 to 20 min. period after acetic acid administration. Thecompound of the present invention was homogeneously suspended in 2%Tween 80/saline for injection use, and was injected intraperitoneally 30min. before the induction by the acetic acid injection. Alternatively,the compound of the present invention was homogeneously suspended in 2%Tween 80/distilled water, and was administrated orally two hours beforethe induction by the acetic acid injection. The analgesic activity ofthe compounds according to the present invention was evaluated on thebasis of the degree of inhibiting the number writhes by theadministration of the compounds. As the positive control, indomethacinor aspirin was administrated. The analgesic activity of the compoundsaccording to the present invention measured in this test wereexemplified in Table 7. TABLE 7 Application Number of CompoundApplication Dose time (min writhes No. route (mg/kg) before) (Mean ±S.E.) Vehicle i.p. — 30 25.2 ± 2.2  Control Vehicle p.o. — 120 23.5 ±3.1  Control 1-41 i.p. 1 30 4.0 ± 1.9 1-41 p.o. 10 120 1.3 ± 0.8 2-29i.p. 1 30 5.5 ± 1.9 2-29 p.o. 10 120 1.5 ± 0.7 Indomethacin i.p. 10 304.8 ± 0.9 Indomethacin i.p. 3 30 13.8 ± 3.0  Indomethacin p.o. 3 60 6.8± 2.0 Aspirin i.p. 30 30 9.5 ± 2.0 Aspirin p.o. 100 60 9.5 ± 1.9

[0177] As it is understood from the results of the foregoingpharmacological tests, it is apparent that the compounds according tothe present invention have excellent inhibitory activities on the PLA(2)activity, being less toxic, having strong anti-inflammatory activitiesand/or anti-allergic activities. Thus, the composites containing thecompounds according to the present invention are useful as therapeuticand/or protective drugs of new type, since sick conditions accompaniedthe activated PLA(2) activity are cured to show excellent effectsagainst such associated diseases, by the administration of thecomposites.

What is claimed is:
 1. A medicinal composition characterized bycomprising as the active ingredient either a compound represented by aformula [I] or a pharmaceutically acceptable composite thereof;

[wherein X represents oxygen or sulfur, Q₁ represents —(CH₂)_(n)— or—CH═CH— (n represents 0, or an integer ranging from 1 to 3), R₁represents hydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl (optionallysubstituted by A₁)—C₁₋₆ alkyl or phenyl optionally substituted by A₁, R₂represents phenyl optionally substituted by A₁, naphthyl optionallysubstituted by A₁, indanyl optionally substituted by A₁,1,2,3,4-tetrahydro naphthyl optionally substituted by A₁, 5 to7-membered heterocyclic group optionally substituted by A₄ containing atleast one heteroatom selected from a group consisting of oxygen, sulfurand nitrogen, R₃ represents hydrogen, C₁₋₆ alkyl optionally substitutedby A₂, C₂₋₆ alkenyl optionally substituted by A₂, C₂₋₆ alkynyloptionally substituted by A₂, C₁₋₆ alkylcarbonyl optionally substitutedby A₂, C₂₋₆ alkenylcarbonyl optionally substituted by A₂, C₁₋₆alkoxycarbonyl optionally substituted by A₂, C₂₋₆ alkenyloxycarbonyloptionally substituted by A₂, C₁₋₆ alkylsulfonyl optionally substitutedby A₂, C₂₋₆ alkenylsulfonyl optionally substituted by A₂, benzoyloptionally substituted by A₃, phenylsulfonyl optionally substituted byA₃, or a group represented by the following formula;

(wherein Q₂ represents —CO—, —CS—, or —S(O)_(m)—, R₆ represents hydrogenor C₁₋₆ alkyl, R₇ represents C₁₋₆ alkyl optionally substituted by A₂,C₂₋₆ alkenyl optionally substituted by A₂, C₂₋₆ alkynyl optionallysubstituted by A₂, C₃₋₇ cycloalkyl optionally substituted by A₄, C₅₋₇cycloalkenyl optionally substituted by A₄, C₁₋₆ alkylcarbonyl optionallysubstituted by A₂, C₁₋₆ alkylsulfonyl optionally substituted by A₂,phenyl optionally substituted by A₃, benzoyl optionally substituted byA₃, phenylsulfonyl optionally substituted by A₃, or 5 to 7-memberedheterocyclic group optionally substituted by A₄ containing at least oneheteroatom selected from a group consisting of oxygen, sulfur andnitrogen, m represents 1 or 2), R₄ represents hydrogen, cyano, a grouprepresented by the following formula; —Q₃—R₈ (wherein Q₃ represents —CO—or —S(O)_(m)—, R₈ represents amino, C₁₋₆ alkyl optionally substituted byA₂, C₂₋₆ alkenyl optionally substituted by A₂, C₂₋₆ alkynyl optionallysubstituted by A₂, C₁₋₆ alkoxy optionally substituted by A₂, C₂₋₆alkenyloxy optionally substituted by A₂, C₂₋₆ alkynyloxy optionallysubstituted by A₂, mono- or di-(C₁₋₆ alkyl)amino optionally substitutedby A₂, C₃₋₇ cycloalkyl optionally substituted by A₄, C₅₋₇ cycloalkenyloptionally substituted by A₄, phenyl optionally substituted by A₃,phenoxy optionally substituted by A₃, anilino optionally substituted byA₃, or 5 to 7-membered heterocyclic group optionally substituted by A₄containing at least one heteroatom selected from a group consisting ofoxygen, sulfur and nitrogen, m represents 1 or 2), R₅ represents nitro,cyano, or a group represented by the following formula; —Q₃—R₈ (whereinQ₃ and R₈ is same as defined in the above description), A₁ representshalogen, nitro, cyano, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, phenyl (optionally substituted by halogen, C₁₋₆ alkyl orC₁₋₆ haloalkyl), pyridyl, thienyl, C₁₋₆ alkoxy, methylenedioxy, C₁₋₆alkylthio, C₁₋₆ alkylsulfenyl, C₁₋₆ alkylsulfonyl, mono- or di-(C₁₋₆alkyl)amino, C₁₋₆ haloalkoxy, benzyl, phenethyl, phenoxy, phenylthio,benzoyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆haloalkylcarbonyl, C₁₋₆ haloalkoxycarbonyl, C₁₋₆ alkylcarbonyloxy,carbamoyl, or mono- or di-(C₁₋₆ alkyl)carbamoyl, A₂ represents halogen,C₁₋₆ alkoxy, C₁₋₆ alkoxy C₁₋₆ alkoxy, amino, mono- or di-(C₁₋₆alkyl)amino, C₁₋₆ alkylcarbonyloxy, C₁₋₆ alkoxycarbonyl, mono- ordi-(C₁₋₆ alkyl)carbamoyl, mono- or di-(C₁₋₆ alkyl)carbonylamino,morpholino, phenyl, or pyridyl optionally substituted by halogen, A₃represents halogen, hydroxy, oxo, mercapto, nitro, amino, cyano, C₁₋₆alkyl, C₁₋₆ haloalkyl, pyridyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆alkylsulfenyl, C₁₋₆ alkylsulfonyl, mono- or di-(C₁₋₆ alkyl)amino, C₁₋₆haloalkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, carbamoyl, mono- ordi-(C₁₋₆ alkyl)carbamoyl, and A₄ represents halogen, hydroxy, oxo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkoxy C₁₋₆alkoxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylsulfonyl, or C₁₋₆alkoxycarbonyl.].
 2. Compounds represented by a formula [I′] orpharmaceutically acceptable composites thereof;

(wherein X, Q₁, R₂, R₃, R₄ and R₅ are same as defined in claim 1, R₁′represents C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl(optionally substituted byA₁)—C₁₋₆ alkyl, or phenyl optionally substituted by A₁; with anexception of the following compounds, provisory; X represents sulfur,both R₁′ and a group represented by R₂—Q₁ represent phenyl, R₃represents methyl, R₄ represents hydrogen, R₅ represents benzoyl; Xrepresents oxygen, R₁′ represents methyl, a group represented by R₂—Q₁represents phenyl, R₃ represents hydrogen, both R₄ and R₅ representcyano; X represents oxygen, R₁′ represents methyl, a group representedby R₂—Q₁ represents phenyl, R₄ represents hydrogen, R₅ representsnitro.).
 3. A process for preparation, characterized by the reactionbismethylthioethylene compounds represented by the following formula[II];

(wherein R₅ is same as defined in claim 1, R₄′ is same as R₄ defined inclaim 1 except for hydrogen), with 2-aminoethanol compounds representedby the following formula [III];

(wherein R₁, R₂, and Q₁ are same as defined as described above), toobtain oxazolidine compounds represented by a formula [I-1];

(wherein R₁, R₂, R₅, R₄′, and Q₁ are same as defined as describedabove).
 4. A process for preparation, characterized by the reaction2-methylthio-2-thiazoline compounds represented by the following formula[IV];

(wherein R₁, R₂, and Q₁ are as defined in claim 1), with activemethylene compounds represented by the following formula [V];R₄′—CH₂—R₅[V] (wherein R₅ is same as defined in claim 1, and R₄′ is sameas defined in claim 3), to obtain thiazolidine compounds represented bya formula [I-2];

(wherein R₁, R₂, R₄′, R₅, and Q₁ are same as defined as describedabove).
 5. A process for preparation, characterized by the reactionoxa(thia)zolidine compounds represented by the following formula [I-3];

(wherein X, R₁, R₂, R₄, R₅, and Q₁ are same as defined in claim 1), withhalide compounds represented by the following formula [VI]; R₃′—Ha1[VI][wherein R₃′ represents C₁₋₆ alkyl optionally substituted by A₂, C₂₋₆alkenyl optionally substituted by A₂, C₂₋₆ alkynyl optionallysubstituted by A₂, C₁₋₆ alkylcarbonyl optionally substituted by A₂, C₂₋₆alkenylcarbonyl optionally substituted by A₂, C₁₋₆ alkoxycarbonyloptionally substituted by A₂, C₂₋₆ alkenyloxycarbonyl optionallysubstituted by A₂, C₁₋₆ alkylsulfonyl optionally substituted by A₂, C₂₋₆alkenylsulfonyl optionally substituted by A₂, benzoyl optionallysubstituted by A₃, phenylsulfonyl optionally substituted by A₃, or agroup represented by the following formula; —S(O)_(m)—NR₆R₇, (whereinR₆, R₇, and m are same as defined in claim 1), Hal represents halogen],to obtain oxa(thia)zolidine compounds represented by a formula [I-4];

(wherein X, R₁, R₂, R₄, R₅, Q₁ and R₃′ are same as defined as describedabove).
 6. A process for preparation, characterized by the reactionoxa(thia)zolidine compounds represented by the following formula [I-3];

(wherein X, R₁, R₂, R₄, R₅, and Q₁ are same as defined in claim 1), withcompounds represented by the following formula [VII]; R₇NCZ [VII](wherein R₇ is same as defined in claim 1, Z represents oxygen orsulfur), to obtain oxa(thia)zolidine compounds represented by a formula[I-5];

(wherein X, R₁, R₂, R₄, R₅, R₇, Q₁ and Z are same as defined asdescribed above).
 7. A composition comprising as the active ingredientat least one selected from a group consisting of heterocyclic compoundsrepresented by the formula [I] and the pharmaceutically acceptablecomposites thereof.
 8. An inhibitor of phospholipase A(2) activitycomprising as the active ingredient at least one selected from a groupconsisting of heterocyclic compounds represented by the formula [I] andthe pharmaceutically acceptable composites thereof.
 9. A use of acomposition for a mammalian which requiring remedy for inflammatorydiseases or disorders, where the composition is characterized bycontaining as the active ingredient at least one selected from a groupconsisting of heterocyclic compounds represented by the formula [I] andthe pharmaceutically acceptable composites thereof.
 10. A method toremedy or reduce inflammatory diseases or disorders, curing and/orpreventing taking turn for the worth by administering a medicinalcomposition, which is comprising an effective dose of at least oneselected from a group consisting of compounds represented by the formula[I] and the pharmaceutically acceptable composites thereof to amammalian requiring treatment.
 11. The method defined in claim 10;wherein the inflammatory diseases or the disorders are any ofanaphylaxis, allergic inflammation, asthma, rhinitis, bronchitis,pneumonia, and adult respiratory distress syndrome, inflammatoryintestine disorder, Crohn's disease, ulcerative colitis,ischemia/reperfusion injuries, vasculitis, arteriosclerosis, hepatitis,nephritis, nerve degenerative diseases, arthritis, dermatitis, solarkeratosis, psoriasis, septic shock and fever.
 12. The method defined inclaim 10, wherein the progress of the sick condition is due toinflammatory disease or disorder that is accompanied with the enhancedphospholipase A(2) activity.
 13. The method defined in claim 10, whereinthe inflammatory disease or disorder is mediated by pro-inflammatorylipid mediators, such as arachidonic acid and the metabolites thereof,and/or lysophosphatidylcholines, and/or platelet activating factor(PAF).
 14. The method defined in claim 10, wherein the pro-inflammatorylipid mediators are suppressed by the inhibitor of phospholipase A(2)activity.
 15. A use of a heterocyclic compound of the formula [I] formanufacturing of a medicinal composition, which is used for reducinginflammatory and/or allergic sick condition and/or sick conditionassociated with immunity, and/or for the remedy of such diseases anddisorders.
 16. A use of a composition as a medicine, where thecomposition contains as the active ingredient at least one selected froma group consisting of heterocyclic compounds represented by the formula[I] and the pharmaceutically acceptable composites thereof.
 17. A use ofa composition as an anti-inflammatory drug, anti-allergic drug and/orimmune controlling drug, where the composition contains as the activeingredient at least one selected from a group consisting of heterocycliccompounds represented by the formula [I] and the pharmaceuticallyacceptable composites thereof.